I'm over the jetlag. I think. The brain fog lifted sometime this am.
The 2 days I spent in Leeds discussing rheumatoid arthritis with 20 rheumatologists from around the world seems like a blur.
One key discussion point needs review and I write down my thoughts today, to help you understand but also to force me to document this before I forget!
In Australia, we are lucky enough to have access to 8 biologic DMARDs once a patient with rheumatoid arthritis is deemed to have severe enough disease and has jumped through a range of hoops to meet set criteria. Now, it would be really nice to be able to work out which medication would be most useful for that individual patient sitting in front of me.
People, patients, respond differently to different therapies. Clinical trial results tell you about how a group responds. Not specifically about the patient sitting in front of me. Of course, we use the scientific evidence that we have to try to make an educated guess. But, it's sometimes not so easy.
With this in mind, I asked the question.
How do you choose what biologic to use?
This diverse group of rheumatologists were from the UK, Spain, Finland, Germany, Russia, Kuwait, Israel, Brazil, Mexico, Columbia, Poland and Australia. There were clinicians and researchers, young and old, those who worked in the public hospital system and those in private practice.
The following is a synthesis of what I took away from the discussion and my own evolving practice.
Please do not take this as prescriptive. There is insufficient clinical trial evidence to be certain and as new head-to-head trials are reported, my approach and choices will likely change.
- The 1st choice tends to be a TNF inhibitor, and the 2 used most commonly are Enbrel (Etanercept) and Humira (Adalimumab). This is not surprising given the TNF inhibitors were the 1st class of biologic agents available for rheumatoid arthritis. Enbrel and Humira were the 1st 2 subcutaneous agents, are generally effective and reasonably well tolerated with good patient registry data over the decade to monitor for safety. Rheumatologists, and doctors in general, tend to be creatures of habit, so it makes sense that they stick with what they know until there is compelling evidence to make them change.
- Remicade (Infliximab), which is a TNF inhibitor that is given intravenously, is used more in places/centres where there is easy access to infusion rooms.
- If the patient does not respond at all to the TNF inhibitor (primary failure), most would change the class of biologic agent. By this, I mean that they would use a non-TNF inhibitor. The choices are Mabthera (Rituximab), Actemra (Tocilizumab), Orencia (Abatacept). Which of these will be used first up after TNF inhibitor failure is quite variable.
Please note that rheumatologists are skilled at taking into account many variables when making a choice.
For example, a rheumatoid patient can have other health issues which make the choice of medication, and in particular, biologic medication tricky.
- If a patient has evidence of latent Tuberculosis (Tb) or is at very high risk of Tb exposure, we would typically treat with drugs to treat the Tb. These would be started prior to the commencement of biologic agent and then overlapped for some months. In the era prior to Tb prophylaxis becoming standard, there were less cases of Tb reported with Enbrel and so for some, that is the TNF inhibitor of choice when Tb is an issue. Some would prefer to use Mabthera as this medication does not seem to increase risk of Tb but most countries do not allow Mabthera to be used as 1st line treatment so access is difficult.
- If there is a history of cancer, it is likely to be safe to use any of the agents if the cancer has been treated and not recurred for at least 5 years. Most however, were keen to use Mabthera (if it was able to be accessed) particularly if the cancer was non-Hodgkin's lymphoma as Mabthera is very effective for that condition.
- If the patient has multiple sclerosis or a family history of such, most would generally avoid TNF inhibitor therapy (but it was noted that the evidence is still uncertain if there is a link between these agents and multiple sclerosis).
- If there is evidence of skin or any other vasculitis, or an overlap syndrome (meaning that the patient seems to be having a combination of different autoimmune disease such as rheumatoid and lupus) or possibly in the setting of chronic leg ulcers, Mabthera would seem a good choice given it's B-cell directed mode of action.
- When there is a high CRP, persistent anaemia, or elevated platelet counts, this may imply high levels of an inflammatory protein called IL-6. It that case, Actemra would probably be a good choice.
- If the patient has Hepatitis B virus infection, we need to avoid Mabthera & there is probably no great option among the other agents in terms of being more safe. Typically, anti-viral treatment will be needed.
- If the patient has Hepatitis C virus infection, the TNF inhibitors seem to be safe.
- If a patient suffers from chronic infections such as bronchiectasis, most would try to avoid TNF inhibitors. A common choice would be Orencia given the feeling that this medication causes less infection.
- When a patient has Interstitial Lung Disease, some would avoid TNF inhibitor therapy and try to access Mabthera instead.
- If the patient already has a prosthetic joint, for eg, a knee replacement, some argued that this would be a relative contraindication for TNF inhibitor use as the infection risk is higher. Especially if, the patient also suffered with chronic leg ulceration.
- Most agreed that Abatacept had a lower rate of infections. In some countries, this medication is not currently used much due to the current lack of availability of the subcutaneous formulation but this will change in the future.
- Mabthera would be a good choice in patients who are seropositive (have positive RF and anti-CCP) and who have hypergammaglobulinaemia (raised levels of a protein called IgG). This does not mean that these patients will not respond to the other agents. Just that these are the characteristics of patients who respond to Mabthera.
- In patients who need treatment while attempting to fall pregnant, the TNF inhibitors are likely to be safe even if the pharmaceutical companies would be unlikely to actively encourage use in this subgroup of patients. Enbrel or Cimzia had been used among the group.
- If very obese patients, subcutaneous biologic patients may not work as well due to poorer absorption.
It's complicated, isn't it?
I again highlight that these are certainly not guidelines. They represent a combination of evidence, some extrapolation of scientific principles, and the clinical experience of a range of rheumatologists.
I hope this gives you some insight as to the amount of thought that your rheumatologist puts into their decision making.
I'd love to hear the thoughts of my rheumatology colleagues reading this.